Submissions for variant NM_000059.4(BRCA2):c.9148C>T (p.Gln3050Ter)

dbSNP: rs80359170

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083155	SCV000301355	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000221883	SCV000279199	pathogenic	not provided	2022-02-19	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9376C>T; This variant is associated with the following publications: (PMID: 22632462, 29506128, 32438681)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000083155	SCV000328068	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000083155	SCV000488214	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771484	SCV000903963	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-25	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 24 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed with a pathogenic CHEK2 covariant in an individual affected with pancreatic cancer with a family history of breast cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV000771484	SCV001180210	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The p.Q3050* pathogenic mutation (also known as c.9148C>T), located in coding exon 23 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9148. This changes the amino acid from a glutamine to a stop codon within coding exon 23. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383878	SCV001583192	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln3050*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52762). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000221883	SCV002774316	pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing	The BRCA2 c.9148C>T (p.Gln3050*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 32438681 (2020), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)) and pancreatic cancer (PMID: 29506128 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000083155	SCV000115229	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-06-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083155	SCV000147552	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2000-07-07	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000083155	SCV001550465	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Gln3050* variant was identified in 1 of 59400 proband chromosomes (frequency: 0.000016) in worldwide study of 29,700 families with BRCA1 or BRCA2 mutations (Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359170) as "With Pathogenic allele", ClinVar (classified as pathogenic by six submitters and likely pathogenic by one submitter), and LOVD 3.0 (2x as pathogenic). The variant was tested in comprehensive splicing functional analysis using bioinformatics analysis of putative splicing and showed minor splicing defects (Acedo 2012). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9148C>T variant leads to a premature stop codon at position 3050 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in BRCA2 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.